Variant 12-28450189-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018318.5(CCDC91):c.791C>A(p.Thr264Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000425 in 1,607,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 0 hom. )

Consequence

CCDC91
NM_018318.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.460

Variant links:

Genes affected

CCDC91 (HGNC:24855): (coiled-coil domain containing 91) Predicted to enable identical protein binding activity. Involved in Golgi to lysosome transport. Located in nucleoplasm and trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

CCDC91 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.019219816).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC91	NM_018318.5 linkuse as main transcript	c.791C>A	p.Thr264Lys	missense_variant	9/13	ENST00000536442.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC91	ENST00000536442.6 linkuse as main transcript	c.791C>A	p.Thr264Lys	missense_variant	9/13	5	NM_018318.5	P1	Q7Z6B0-1

Frequencies

GnomAD3 genomes

AF:

0.000303

AC:

AN:

151670

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000606

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000392

AC:

AN:

247612

Hom.:

AF XY:

0.000372

AC XY:

AN XY:

134306

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000326

Gnomad NFE exome

AF:

0.000776

Gnomad OTH exome

AF:

0.000502

GnomAD4 exome

AF:

0.000437

AC:

637

AN:

1456068

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

322

AN XY:

724498

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000338

Gnomad4 NFE exome

AF:

0.000533

Gnomad4 OTH exome

AF:

0.000449

GnomAD4 genome

AF:

0.000303

AC:

AN:

151670

Hom.:

Cov.:

AF XY:

0.000311

AC XY:

AN XY:

74054

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.000606

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000750

Hom.:

Bravo

AF:

0.000291

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000552

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2024

The c.791C>A (p.T264K) alteration is located in exon 8 (coding exon 8) of the CCDC91 gene. This alteration results from a C to A substitution at nucleotide position 791, causing the threonine (T) at amino acid position 264 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.034

.;T;.;T;T

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.74

T;T;T;.;T

M_CAP

Benign

0.0088

MetaRNN

Benign

0.019

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.20

.;.;.;N;N

MutationTaster

Benign

0.65

N;N;N;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.1

N;N;N;N;N

REVEL

Benign

0.082

Sift

Benign

0.16

T;T;T;T;T

Sift4G

Uncertain

0.016

D;T;T;T;T

Polyphen

0.0, 0.041

.;.;B;B;B

Vest4

0.21, 0.20, 0.18

MVP

0.43

MPC

0.094

ClinPred

0.057

GERP RS

5.1

Varity_R

0.16

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over